Although lithium carbonate was discovered to be an effective antimanic agent by John Cade in 1949, it was not approved for general use in the U.S. until 1969. Lithium is highly specific in its alleviation of manic symptoms, normalizing the mood of manic patients rather than compensating for the excesses of the manic state through sedation or "tranquillization". In addition, it is perhaps the only drug in psychiatry for which clear prophylaxis against disease recurrences and deterioration has been demonstrated. Recent evidence suggests that lithium may also be effective in treating nonbipolar depressive illness and even in the treatment of psychotic disorders other than mania. However, its clearest effects are in bipolar disorder. Bipolar disorder includes both mania and depression, or only mania. Bipolar has been further divided into Bipolar I and II. In the former cases, there is presence of a full-blown manic episode, and in the latter case there is mild hypomania only.
Despite its remarkable and undisputed therapeutic properties, a number of issues detract from the therapeutic utility of lithium. Antipsychotic drugs are the first pharmacologic mode of treatment of acute bipolar disorder, unless the patient is manageable enough to wait the 7-10 days it takes for lithium to exert its antimanic effect. A costly prelithium workup is required because of the adverse effects common to lithium therapy. Lithium can cause a transient leukocytosis, can cause patients with a borderline thyroid reserve to become clinically hypothyroid, and can decompensate cardiac status due to shifts in fluids and electrolytes. Notably, the polyuria-polydipsia syndrome occurs in up to 60% of treated patients. Structural lesions in kidney, including interstitial fibrosis, tubular atrophy and glomerular sclerosis, are reported after chronic lithium treatment, especially in patients who have experienced lithium toxicity. Other adverse effects of lithium include tremor, weight gain, diarrhea and skin rash. These side effects are serious practical deterrents to the use of lithium in clinical practice.
Side effects, especially the more serious ones, can be reduced by monitoring plasma lithium concentrations in bipolar patients. The need to monitor plasma drug concentrations, and to maintain these within a narrow therapeutic range, detract from its clinical utility.
An ideal lithium mimetic agent would have a rapid onset of action in both bipolar and non-bipolar depression, require only once-a-day dosing, and have a safety profile requiring no extensive pretreatment medical evaluation, no plasma drug monitoring, nor be associated with as severe a spectrum of side effects as lithium, per se.
The identification of the phosphoinositide (PI) cycle as a likely target for lithium action arose from the work of Sherman and colleagues, who demonstrated a profound elevation of inositol-1-phosphate and a corresponding decrease in free inositol in the brains of rats treated systemically with lithium. This was attributed to inhibition of inositol-1-phosphate phophatase and led to the hypothesis that lithium was able to damp down the activity of the PI cycle in overstimulated cells, thus possibly explaining its effectiveness in the control of mania. An attraction of the hypothesis is that it was able to offer an explanation for the CNS selectivity of lithium action. Provision of inositol for the PI cycle can come from hydrolysis of inositol phosphates, by de novo synthesis from glucose, or from the diet. The former processes are dependent on the operation of inositol-1-phosphate phosphatase and are, therefore, inhibited by lithium. Dietary inositol can bypass lithium blockade in peripheral tissues but not in the CNS, since inositol does not cross the blood brain barrier. Thus, the increase in inositol-1-phosphate in brain is accompanied by an equivalent decrease in free inositol.
It appears that lithium interferes with inositol polyphosphate second messenger production and breakdown in animals. There is substantial support for this idea from work with isolated cells and tissues. Thus development of potent and specific inhibitors of inositol monophosphate phosphatase, could lead to completely novel drugs effective for the treatment of mania and depression.
Hydrolysis of the second messenger D-Ins(1,4,5)P.sub.3 proceeds through D Ins(1,4)P.sub.2 and D-Ins(4)P. The putative second messenger D-Ins(1,3,4,5)P.sub.4 is hydrolysed in a similar way to D-Ins(3,4)P.sub.2 via D-Ins(1,3,4)P.sub.3 and then to D-Ins(3)P. Inositol-1-phosphate phosphatase, from bovine brain, purified to homogeneity is shown to be responsible for the hydrolysis, not only of D-Ins(1)P, but also of D-Ins(3)P (the intermediate for synthesis of inositol from glucose-6-phosphate, also known as L-Ins(1)P), D-Ins(4)P and its unnatural enantiomer, L-Ins(4)P. The enzyme is non-competitively inhibited by lithium and kinetic studies are compatible with binding of lithium to a phosphoenzyme intermediate, preventing its hydrolysis.
Kaise et al in J. C.S. Chem. Comm. (1979) p. 726-7 describes K-76 an inhibitor for the complement system which participates in rheumatoid arthritis, glomerulonephritis and other immune complex diseases. K-76 was obtained from Stachybotrys complementi nom. nud. sp. K-76 and has the structure: ##STR3##